Nitric Oxide (NO) plays a variety of roles in a number of physiological processes. In fact NO can be viewed as a double-edged sword in terms of its biological functions. On one hand, NO exerts beneficial regulatory effects in a variety of tissues. For example, NO has well-characterized vasoactive properties (see, for example, Martin, J.; Angeles, M. R.-M. Pharmocol. Ther. 1997, 75, 111; Pfeiffer, S.; Mayer, B.; Hemmens, B. Agnew. Chem., Int. Ed. 1999, 38, 1714; Furchgott, R. F. Agnew. Chem. Int. 1999, 38, 1870). Also, the role of NO as a neurotransmitter has been thoroughly explored (see, for example, Hibbs, J. B.; Taintor, R. R.; Varvin, Z. Science 1987, 235, 473; Nathan, C.; Hibbs, J. B. Curr. Opin. Immunol. 1991, 3, 65). In addition, NO plays a role in host defense systems. For example, nitric oxide is generated in response to a variety of stimuli (see, Hibbs, J. B., Westenfelder C., Taintor R. et al., J. Clin Invest 1992, 89, 867; Bukrinsky M.; Schmidtmayerova H.; Zybarth G.; Dubrovsky L., Sherry B.; Enikolopov G., Mol Med 1996, 2, 460; Zambala M.; Siedlar M.; Marcinkiewicz J.; Pryjma J. Eur J Immunol 1994, 24, 435), including bacteria and cytokines (see, Denis M.; J Leukoe Biol 1991, 49, 380). Furthermore, macrophages, kupffer cells, natural killer cells, and endothelial cells participate in tumoricidial activity, at least in part, by producing NO (Garthwaite, J.; Charles, S. L.; Chess-Williams, R., Nature 1988, 336, 385; Gillespi, J. S.; Liu, X.; Martin, W., Br. J. Pharmocol. 1989, 98, 1080).
NO can be easily converted into a variety of reactive nitrogen species (RNS), such as N2O3, NO2 and ONOO−(peroxynitrite anion). While these RNS are highly reactive, their reactivity can be utilized to achieve beneficial results. For example, peroxynitrite anion is a potent oxidizing and nitrating species capable of inducing molecular damage in DNA, such as strand breaks. Sufficient generation of this RNS can lead to cellular dysfunction, up to and including cytotoxicity (see Koppenol, W. H., Free Radic, Biol. Med, 1998, 25, 385-391; Murphy, M. P.; Packer, M. A.; Scarlett, J. L. ; Martin, S. W., Gen. Pharmacol. 1998, 31, 179-186; Douki, T.; Cadet, J.; Ames, B. N., Chem Res. Toxicol. 1996, 9, 3-7). By controlling the generation of this RNS to a localized area in which it is desirable to kill cells, such as in a solid tumor, the reactivity of peroxynitrite anion can be used to achieve a desired result.
As a result, targeted or specific delivery of NO to a site of interest could provide a useful mechanism to harness the reactivity of various RNS. Although delivering NO in its gaseous form may have some benefits (see, Nelin L; Moshin C; Sasidharan T; Dawson C, Pediatric Research 1994, 35, 20 Etches P; Finer K; Barrington A; Graham A; Chan W, Pediatric Research 1994, 35, 15), NO gas is highly reactive itself in a generally nonspecific manner. To utilize the cytotoxic effects of NO in a selective manner, NO must be delivered to the targeted cells or sites while minimizing exposure to those not targeted.